# Macrophage Dysfunction in Obesity, Diabetes and Atherosclerosis

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $2,430,175

## Abstract

Accumulation of inflammatory macrophages is a common feature in adipose tissue (AT) and other metabolic
organs and in the atherosclerotic plaque. Diabetes further exacerbates macrophage content and inflammation,
which in mouse models impairs atherosclerosis regression; and in obesity, drives insulin resistance. The
overarching hypothesis of this Program is that there are factors and pathways underlying macrophage
accumulation and inflammation in atherosclerotic plaques and AT that are tissue site-independent,
representing common mechanisms, as well as tissue site-dependent, representing discrete regulation by the
local micro-environments. Our Program will test the mechanisms affecting plaque or AT macrophage content
and inflammatory states in diabetes or diet-induced obesity in relation to four key processes: recruitment of
monocytes, macrophage retention/stasis, macrophage inflammation/polarization (M1 vs. M2), and macrophage
regulation of metabolism. To accomplish this, we have developed three Projects as follows: Project 1 will test
these concepts in diabetic atherosclerosis in the context of impaired regression after reduction of
hyperlipidemia; and Projects 2 and 3 will test these concepts in diet-induced obesity mediated by high fat
feeding. In this highly synergistic Program, through coordinated and systematic studies, each Project will
identify the connections, cross talk, and regulatory hierarchies in the diabetic and pre-diabetic insulin resistant
states by which candidate and novel factors drive macrophage content and inflammation. By comparing the
results across the plaque and AT, we will identify those pathways that underlie both common and distinct
mechanisms. All three Projects will test the relevance of findings in mouse macrophages to curated databases
of human monocytes/macrophages and of AT macrophages retrieved from lean and obese human subjects. In
“proof-of-concept” studies, all three Projects will test novel therapeutic agents targeting the key pathways
under study in mouse models in a highly synergistic manner. Taken together, our ultimate goal is to identify
novel therapeutic approaches to suppress exaggerated macrophage accumulation and inflammation that
contribute to increased clinical cardiovascular risk.

## Key facts

- **NIH application ID:** 9925242
- **Project number:** 5P01HL131481-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Edward A Fisher
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,430,175
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925242

## Citation

> US National Institutes of Health, RePORTER application 9925242, Macrophage Dysfunction in Obesity, Diabetes and Atherosclerosis (5P01HL131481-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9925242. Licensed CC0.

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